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Identification of Estrogen Regulated Metastasis-Associated Genes Involved in Breast Cancer Bone Metastases
Bone is one of the most frequent sites for metastasis in breast cancer patients. None of the currently available therapies is effective for curing or preventing bone metastases.
Estrogens (E2) play an important role in the biology of breast cancer via activation of estrogen receptors (ER). It has been shown that patients with ERa-positive tumors are three times more likely to develop bone metastases than patients with ERa-negative tumors. The role of ERb is uncertain. Both breast and bone tissues express two ER subtypes: ERa and ERb. Our hypothesis is that since the two ERs have different tissue distribution and subtype-selectivity at gene sites, the biological roles of ERa and ERb in the development and progression of bone metastasis can differ. Selective ER Modulators (SERMs) that are used for breast cancer treatment and prevention demonstrate significant differences in activity, functioning as E2 agonists in some tissues, but as antagonists in others. Very little is known about the exact role of E2 and SERMs in bone metastasis.
The molecular mechanisms responsible for bone metastases are complex and involve bi-directional interactions between tumor cells and bone. During this interaction the ability for cancer cells to grow and colonize depends on metastasis-associated factors released by both bone and cancer cells. Many of these factors are known to be E2-responsive. However, the roles of ERa and ERb are not understood, partially because there are very few ER-positive in vitro and in vivo models of breast cancer bone metastases.
Our purpose is to identify E2-regulated metastasis-associated factors necessary for successful bone metastases. We aim 1) to establish and characterize an in vitro hormone–responsive co-culture system, which consist of ERa/b – positive metastatic breast cancer cells and ERa/b–positive bone cells; 2) to identify expression profiles of ERa/b-mediated metastasis-associated genes in order to determine the effects of E2/SERMs on the interaction between cancer cells and bone cells in various co-culture systems; 3) define the contributions of selected genes and ER-signaling pathways in pathophysiology of osteoblastic/osteolytic bone metastases of breast cancer.
Understanding cellular and molecular mechanisms of hormone dependent breast cancer bone metastases is prerequisite for the development of effective therapeutic interventions for the prevention and treatment of bone metastases. Results of this study can influence the strategy of hormonal therapy for advanced metastatic disease.
Most breast cancer patients die not because of the initial tumor, but because it spreads to other parts of their body. Bone is one of the most frequent sites the disease attacks in breast cancer patients – 65 to 85% - resulting in fatality. Bone metastases are also usually associated with severe bone pain. They cause fractures and other symptoms and complications that can dramatically affect the patient’s lifestyle. None of the currently available therapies is effective for curing bone metastases in these patients.
The role of estrogens in the biology of breast cancer is well established; however, the role of estrogens and selective estrogen receptor modulators (SERMs), a new class of drugs, in advanced metastatic disease is unknown. Estrogens and SERMs bind and activate two distinct proteins, estrogen receptor a (ERa) and ERb, which are expressed in both breast and bone tissues. In the process of interaction between metastatic cancer cells and bone cells, which determines the outcome of metastases, there is an activation or repression of ER-mediated pathways by hormones. This interaction, which is called a „vicious cycle”, involves production of metastasis–associated factors that promote both cancer cell growth and bone breakdown. We propose to examine diverse biological functions of ERa and ERb using the model system for hormone-responsive bone metastases and to identify estrogen-regulated bone metastasis-associated factors. Identification of these factors will enable us 1) to distinguish “good” ER-positive tumors from “bad” ER-positive tumors with potential to metastasize to bone and 2) to select and suggest possible targets for therapeutic intervention.